PROJECT DESCRIPTION/ABSTRACT Based on the 2016 American Heart Association report, there are about 550,000 Americans newly suffering from myocardial infarction (MI) (defined as first hospitalized MI) and 200,000 recurrent cases. Approximately, one American will have an MI every 42 seconds. While many factors contribute to the prognosis of MI patients, two major determinants are the initial infarction size and the efficiency of the post-MI recovery process. Clinically, modern percutaneous coronary intervention (PCI), known as angioplasty, significantly decreases the extent of the infarction. However, the subsequent wound healing processes, which are initiated and driven by dynamic sterile inflammation, are complicated and elusive. A better understanding of sterile inflammation molecular regulation during acute MI is highly significant, and lays the foundation for all stages of post-MI therapeutics. In this proposal, we have developed a cardiac-specific RhoE (a small G protein, also called Rnd3) deficient- mouse line that is susceptible to MI. RhoE haploinsufficient mice exhibit an intense inflammatory response with compromised cardiac function after MI. We propose multiple systemic approaches including in vitro analysis of protein-protein interactions, cell culture experiments, and in vivo genetic animal assessments with loss- and gain-of-function strategies to investigate the relationship between the expression levels of RhoE and the regulation of post-MI inflammation. The detailed molecular mechanism of RhoE-mediated sterile inflammation regulation will be elucidated. For the first time, RhoE is linked to inflammation regulation. We suggest that RhoE is a new ?fine-tuning? factor situated at the nexus of the inflammatory response, and is responsible for balanced sterile inflammation after acute MI. The animal models include heart specific conditional RhoE-deficient mice as well as heart specific RhoE- overexpression transgenic mice. The mechanistic findings from this proposal should result in clinical implications given the fact of significant downregulations of RhoE in heart failure patients. The discovery will provide a foundation for future pharmacological translation.